miR-29a-3p Attenuates Hypoxic Pulmonary Hypertension by Inhibiting Pulmonary Adventitial Fibroblast Activation

Abstract

H ypoxic pulmonary hypertension (HPH) is still a lifethreating disorder lack of effective agents. It is highly prevalent in advanced chronic obstructive pulmonary disease and high altitude hypoxia. With the increase of chronic obstructive pulmonary disease patients, the morbidity of HPH is rising. Although most of HPH is mild to moderate, a subpopulation (1%-4%) with grim prognosis present with severe pulmonary hypertension.1 Pharmacological agents moderately improve the symptoms and hemodynamic parameters of severe pulmonary hypertension, but none significantly reduces mortality. 2,3 There is a pressing need to identify novel target to treat HPH.One of the characteristics of HPH is the dramatic remodeling of pulmonary vascular adventitia. 4,5 During the remodeling, pulmonary adventitial fibroblasts (PAFs) are highly activated and undergo phenotype switch characterized by excessive proliferation, migratory, and inflammatory activity. 6,7 Therefore, inhibition of the aberrant activation of PAFs may reverse the remodeling process of pulmonary vascular adventitia and have therapeutic potential for HPH. 8 Increasing evidence shows that miRNAs, especially miR-29 family members, participate in the development of organ fibrosis via regulating the activation of fibroblasts. 9-11Downregulation of miR-29 underlies transforming growth factor-β-mediated pulmonary fibrosis, and overexpression of miR-29 inhibits bleomycin-induced pulmonary fibrosis. 12 Although PAFs in HPH undergo the similar activated phenotype to that in lung fibrosis, 6 the role of miR-29 family member in the hypoxia-induced activation of PAFs and the development of HPH is not known. On the other hand, hypoxia-inducible factor-1α (HIF-1α), a key transcription factor mediating cellular response to hypoxia, and Smad3, which can inhibit miR-29 expression in organ fibrosis, are interdependent in hypoxia. [13][14][15][16] Therefore, HIF-1α and Smad3 may be jointly involved in the regulation of miR-29 in the activation of PAFs in hypoxia.The present study explored the effects of miR-29a in the activation of PAFs in hypoxia and the therapeutic potential in HPH. The results show that miR-29a-3p plays a key role in hypoxia-induced activation of PAFs and has protective effects in HPH in rats.Abstract-Activation of pulmonary adventitial fibroblasts plays a key role in the pulmonary vascular remodeling in hypoxic pulmonary hypertension. Previous studies showed that miRNAs participated in the regulation of fibroblast activation. This study explored the role of miR-29 in the activation of pulmonary adventitial fibroblasts and the therapeutic potential in hypoxic pulmonary hypertension. We found that hypoxia-induced pulmonary adventitial fibroblasts activation was accompanied with a drastic decrease of miR-29a-3p expression. Knockdown of hypoxia-inducible factor-1 α or Smad3 reversed the hypoxia-induced decrease of miR-29-3p in cultured pulmonary adventitial fibroblasts. In vitro, miR-29a-3p mimic inhibited the hypoxia-induced proliferation, migration, and secretion of p...

Upregulation of miR-335-3p by NF-κB Transcriptional Regulation Contributes to the Induction of Pulmonary Arterial Hypertension via APJ during Hypoxia

“…Recently, miRs have been strongly associated with development and progression of PAH and the modulation of its pathophysiological function [10,11]. Moreover, they exhibit essential roles in both proliferation and migration of PASMCs, as well as vascular remodeling in PAH during hypoxia, as have been reported by a number of elegant studies [12][13][14][15][16][17][18][19][20][21][22]. Although miRs are known major upstream regulators of many key target genes involved in hypoxic PAH development, the transcriptional regulation of miRs by critical effectors on PAH during hypoxia is less clear.…”

MicroRNAs and Endothelial (Dys) Function

“…Studies in rodents greatly contributed also to the identification of several miRs implicated in the pathogenesis of pulmonary hypertension, including miR‐21, miR‐26a, miR‐29a‐3p, miR‐30c, miR‐17‐92, miR‐96, miR‐125a, miR‐126, miR130‐301, miR143/145, miR‐204, miR‐206, miR‐210, miR‐223, miR‐424, and miR 503 (Kim et al, ; Potus et al, ; Courboulin et al, ; Luo et al, ; Meloche et al, ; Schlosser et al, ; Tang et al, ). However, discordant results have been found when comparing preclinical and clinical studies, due to the existence of multiple experimental models of pulmonary hypertension (Schlosser et al, ).…”

MiR-19b-3p Regulates MAPK1 Expression in Embryonic Fibroblasts from the Great Tit (Parus Major) Under Hypoxic Conditions

“…For example, miR-29a-3p decreases hypoxia-induced pulmonary hypertension activity and inhibits pulmonary adventitial fibroblast activation [31]. Another miRNAs, miR-205, promotes the epithelial-mesenchymal transition process in response to hypoxia and may be a therapeutic biomarker of cervical and lung cancers [11].…”